This invention relates to the use of Salmonella vectors in vaccination methods against Helicobacter infection.
Helicobacter is a genus of spiral, gram-negative bacteria that colonize the gastrointestinal tracts of mammals. Several species colonize the stomach, most notably H. pylori, H. heilmanii, H. felis, and H. mustelae. Although H. pylori is the species most commonly associated with human infection, H. heilmanii and H. felis have also been isolated from humans, but at lower frequencies than H. pylori. Helicobacter infects over 50% of adult populations in developed countries and nearly 100% in developing countries and some Pacific rim countries, making it one of the most prevalent infections worldwide.
Helicobacter is routinely recovered from gastric biopsies of humans with histological evidence of gastritis and peptic ulceration. Indeed, H. pylori is now recognized as an important pathogen of humans, in that the chronic gastritis it causes is a risk factor for the development of peptic ulcer diseases and gastric carcinoma. It is thus highly desirable to develop safe and effective methods for preventing and treating Helicobacter infection.
The invention provides a method of inducing an immune response against Helicobacter in a mammal. This method involves mucosally (e.g., orally) administering to a mammal (e.g., a human) an attenuated Salmonella (e.g., S. typhi (e.g., CVD908-htrA or CVD908) or S. typhimurium (e.g., BRD509 or BRD807)) vector including a nucleic acid molecule encoding a Helicobacter antigen (e.g., a urease, a urease subunit, or an immunogenic fragment thereof), and parenterally administering to the mammal a Helicobacter antigen (e.g., a urease, a urease subunit, or an immunogenic fragment thereof), optionally, in association with an adjuvant, such as an aluminum compound (e.g., alum). The nucleic acid molecule encoding the Helicobacter antigen can be under the control of a promoter, such as an htrA or a nirB promoter. The antigen used in the mucosal administration can be different from, cross-reactive with, or, preferably, identical to the parenterally administered antigen. In a preferred embodiment, the mucosal administration primes an immune response to an antigen, and the parenteral administration boosts an immune response to the antigen. A mammal treated according to the method of the invention can be at risk of developing, but not have, a Helicobacter infection, or can have a Helicobacter infection. That is, the method can be used to prevent or to treat Helicobacter infection.
The invention also provides an attenuated Salmonella (e.g., S. typhi (e.g., CVD908-htrA or CVD908) or S. typhimurium (e.g., BRD509 or BRD807)) vector including a nucleic acid molecule encoding a Helicobacter antigen, e.g., a urease, a urease subunit, or an immunogenic fragment thereof, expressed as a fission protein that can be selectively targeted to the outer membrane or secreted from the cell. The nucleic acid molecule encoding the Helicobacter antigen can be under the control of a promoter, such as an htrA or a nirB promoter.
Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims.